It is well known in the art that different crystalline forms can be obtained due to the differences in crystallization solvents and methods, e.g., crystallization temperature, cooling rate, stirring or standing, and that different crystalline forms may have different stability and solubility, sometimes even different in vivo bioavailability. Accordingly, it is necessary to obtain a crystalline form with high purity and is thermodynamically stable in the development of a drug, and the method of making the crystalline form may be easily reproduced and is suitable for industrial scale preparation. In addition, X-ray powder diffractometry(XRPD), infrared spectroscopy (IR), differential scanning calorimetry(DSC), and thermal gravimetric analysis (TG) are effective means of characterizing crystalline forms.
Apremilast (Compound I, chemical name is (+)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1,3-dione) is a phosphodiesterases 4 (PDE4) inhibitor which acts on Adenosine 3′,5′-cyclic monophosphate (cAMP), wherein inhibition of PDE4 can result in increased intracellular cAMP levels, thereby alleviating arthrocele and improving the physiological function of j oints. The structure of Apremilast is shown below:

This drug has been approved for treating psoriatic arthritis in US in March 2014 and approved for treating psoriasis in September of the same year. Crystalline forms of the drug have been reported in CN102702070A; this patent disclosed seven solid forms or crystalline forms of Apremilast, namely Forms A, B, C, D, E, F, and G, the XRPD patterns, DSC patterns, and TGA patterns of said forms are summarized in Table 1 below.
Amongst the crystalline forms, Forms C, D, E, and G are solvates and are not suitable for use in medicine; Forms A, B, and F are non-solvates or substantially free of solvents. This patent disclosed the conversion between different crystalline forms, but did not provide any working example of preparing each crystalline form, thus cannot be reproduced.
TABLE 1Data of Apremilast crystalline forms reported in CN102702070ASolidCrystallization solvents andDSCTGAformsmethodsCharacterizing XRPD peakspatternpatternAAcetone, ethyl alcohol or their8.1, 14.4, 15.2, 17.4, 18.4,147° C.0.05%combination, rapid cooling and19.2, 20.5, 22.8, 23.2, 23.6,158° C.crystallization24.5, 25.1Bisopropanol, acetone,10.1, 12.4, 13.5, 15.7, 16.3,157° C.0.25%acetonitrile, ethyl alcohol,18.1, 20.7, 22.5, 24.7, 26.2,ethyl acetate, heptane,26.9, 29.1methanol, butanone, methyltertiary butyl ether,dichloromethanen-butylalcohol, n-butyl acetate,THF, toluene, water, oracetone + ethyl alcohol, ethylalcohol + waterCacetone, acetonitrile, ethyl7.5, 11.3, 15.3, 16.4, 17.8,153° C.5.95%alcohol, heptane, methanol,21.4, 22.6, 23.5, 24.8, 25.5,187° C.toluenebutanone, THF, toluene, water26.4, 27.6solvateor a combination of two ormore of the above solvents;Ddichloromethane7.5, 9.6, 11.3, 13.9, 16.3,104° C.6.5%17.7, 20.5, 23.2, 24.6, 25.2,dichloro26.0, 28.8methanesolvateEacetone, acetonitrile, heptane,7.6, 9.2, 11.4, 15.5, 16.5,100° C.4.0%,dichloromethane, or a17.9, 19.6, 20.5, 21.6, 22.8,acetonitrilecombination of two or more of23.8, 26.6solvatethe above solvents;Fethyl alcohol, acetone, water, or8.1, 8.6, 15.6, 17.3, 19.3,149° C.0.06%a combination of two or more21.4, 22.8, 24.6, 25.4, 25.9,of the above solvents;26.6Gethyl acetate7.9, 9.5, 11.7, 15.7, 16.8,112° C.3.62%,18.1, 19.7, 21.8, 22.8, 25.1,ethyl25.8, 26.7acetatesolvate
Amongst the Forms A, B, C, D, E, F, and G disclosed in CN102702070A and the registration file submitted to the EMEA by Celgene, it is believed that Form B is the most thermodynamically stable form, which is suitable for storage and preparation processing. However, Otezla, which is sold by Celgene, has a shelf life of merely one year, which is a disadvantage for a commercial product. Thus, there is the need to obtain a more thermodynamically stable crystalline form that is suitable for long term storage of the API and preparations, and said crystalline form does not affect the in vivo bioavailability, or even has a better in vivo bioavailability than the known crystalline forms.